This project which has been supported as a program project grant from NIEHS has the overall goal of defining mechanisms of injury to humans from the oxidant air pollutant ozone. The project has clearly established that the pathologic biologic response of the mammalian respiratory system to inhalation of ambient concentrations of ozone a) focuses on the epithelial populations lining airspaces; b) varies by species (with monkeys being more susceptible than rats and hamsters); c) varies by position within the airway tree; and d) changes in nature with duration to exposure. The program is currently organized around the premise that continued exposure to ozone or other oxidant pollutants fundamentally alters the biological homeostasis of the respiratory system. This is a multidisciplinary, highly interactive, research group utilizing cellular biological, pathobiological, biochemical and molecular approaches to defining fundamental mechanisms to ozone injure and repair in the respiratory system. Major findings during the last research period include the establishment of methodologies to quantitatively define changes in intracellular free radical production, glutathione pools and cellular permeability on a cell-by-cell basis, using fluorochromes as substrates and markers and confocal microscopy for imaging. This approach is allowing us to define the relation of intracellular GSH pools to cellular injury by oxidant gases. We have also established that one of the important roles of neutrophils in acute inflammation is the promotion of alveolar epithelial repair. We have also established an isolated perfused lung model using lobes of rhesus monkey lung. We have found the alterations in breathing patterns produced by airways hyperactivity modulates the local ozone doses to tissue and the subsequent injury.